Both memory and addiction produce long-lasting changes in behavior and result in chronic neural adaptations in response to repeated neural activity. It is therefore likely that memory and addiction recruit some of the same molecular mechanisms of synaptic plasticity in the same neural structures. In the present proposal, we explore the parallels between addiction and memory by examining the impact of genetic and anatomical manipulations known to affect memory on addiction-related behavioral plasticity. In a simple behavioral paradigm in mice we can rapidly quantify psychomotor sensitization to repeated cocaine injections, as well as the conditioned response to cues associated with cocaine administration, the contextual control over the expression of cocaine sensitization, and conditioned place preference induced by cocaine. First, we use this paradigm to evaluate the role of the hippocampus and amygdala in addiction-related memory. Second, we use inducible and region-specific disruption of calcium/calmodulin- dependent protein kinase II (CaMKII), a criticial kinase in memory formation, in addiction. Finally, we examine the role of calcium calmodulin in addiction. A benefit of using modern genetic manipulation is the ability to better localize key neuroadaptations through disruption of dendritic translation, and inducible region-specific disruption of alpha-CaMKI in the forebrain and striatum. The inducible and reversible molecular manipulations we propose, post-induction disruption of CaMKII or calcium calmodulin, actually have the potential to reverse sensitization to cocaine and related memories. Taken together, these studies will evaluate the parallels between memory and addiction-related behavioral plasticity and shed considerable light on whether manipulations of memory will prove useful in the treatment of addiction.Project Narrative Addiction is a major social and medical problem affecting millions of compulsive drug users. In the present proposal we examine the relationship between memory and addiction at the level of the brain. If memory and addiction prove to be highly related, disruptions of memory may prove highly useful in the treatment of addiction. [unreadable] [unreadable] [unreadable]